This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the current reporting period we confirmed that CD137-mediated signaling, an event that leads to protective immune responses by T cells, under appropriate conditions induced suppression of T cell function (anergy). By adoptive transfer of CD137-sufficient SMARTA transgenic CD4 T cells and CD137-sufficient P14 TCR transgenic CD8 T cells into CD137-deficient mice we have learned that CD137-mediated anergy was dependent on CD137 expression on T cells, but while necessary, was insufficient to induce T cell anergy. CD137 signaling in T cells led to up- regulation of the apoptosis-inducing death receptor CD95 (Fas). While examining the function of other hematopoietic cell lineages, we found that CD137-mediated signaling in dendritic cells (DC) was critical to the induction of anergy in virus-specific T cells, and that all major subsets of DCs expressing CD137 could induce T cell anergy. Anergic T cells are ultimately deleted through a process known as activation-induced cell death (AICD) and this process too is DC and CD137-dependent as it induces the upregulation and release of soluble Fas ligand by T cells. From studies geared to understand how CD137 signaling in DCs altered their function such that these antigen-presenting cells led to the induction of anergy and AICD rather than as is normal, the activation of na[unreadable]ve T cells, we found that CD137 signaling in DCs led to the rapid activation (phosphorylation) of the transcription factor, Stat3. Others had previously shown that Stat3 signaling in DCs plays a critical role in the maintenance of immune self-tolerance. Current studies are currently underway to indentify the biochemical pathway through which CD137 activates Stat3.